PROJECT 3 - IGF-I and Neuroendocrine Regulation of Female Reproductive Function

本项目验证了胰岛素样生长因子-1（IGF-1）及其受体是必不可少的喜剧演员的假设 雌二醇（E2）在神经内分泌下丘脑（HYP）中的关键生殖作用。我们 已经表明，慢性脑室内输注IGF-1受体拮抗剂抑制发情， 周期，这是一种不归因于食物摄入受损或体重减轻的效应。因此 提出的实验验证了HYP中IGF-1受体信号传导对于 E2对女性生殖功能的神经内分泌调节。我们将确定机制和神经 IGF-1调节下丘脑-垂体-性腺轴的位点，通过确定IGF-1是否起作用 直接作用于促性腺激素释放激素（GnRH）神经元、其传入输入和/或其 对E2的反应。最后，我们将检验延迟和减弱的黄体生成 雌性大鼠向生殖衰老过渡的特征性激素（LH）激增， 与衰老大脑中IGF-1受体信号传导减少有因果关系。具体目标1检验假设 IGF-1对E2依赖性LH峰的调节是在HYP水平介导的，而不是在 脑垂体具体目标2检验IGF-1调节E2依赖性GnRH传入信号的假设 神经元我们将确定脑IGF-1受体阻断剂对GnRH神经元激活的影响， 荷尔蒙状况会导致LH激增我们还将确定脑IGF-1的影响， 受体阻断剂对E2调节HYP中E2受体和Kisspeptin基因表达的影响， 内侧视前区兴奋性（谷氨酸）和抑制性（GABA）神经递质释放 GnRH细胞体的位点）。具体目的3检验IGF-1调节GnRH神经元的假设 对E2传入输入的反应。我们将确定脑IGF-1受体阻断剂对 谷氨酸，kisspeptin和α 1-肾上腺素能激活LH释放的雌激素。具体目标 4检验了生物可利用的IGF-1水平下降与延迟和 在中年女性生殖衰老的过渡减弱LH激增。我们将 确定是否升高脑IGF-1恢复中年大鼠的LH依赖性激增， 因此，这种操作是否也恢复了氨基酸神经传递和kisspeptin的E2调节， 基因表达。这些发现可能有助于深入了解卵巢早衰的潜在机制。 失败和生殖神经内分泌功能障碍，伴随糖尿病和多囊卵巢 综合征（PCOS）。这可能为治疗生殖障碍提出新的治疗策略 与IGF-1水平改变有关，如PCOS。他们还可以确定那些操纵 可能会延长中年妇女接触卵巢类固醇的生理益处

This project tests the hypothesis that insulin-like growth factor-1 (IGF-1) and its receptor are essential comediators of critical reproductive actions of estradiol (E2) in the neuroendocrine hypothalamus (HYP). We have shown that chronic intracerebroventricular infusion of an IGF-1 receptor antagonist suppresses estrous cycles, an effect that is not attributable to impaired food intake or reduced body weight. Therefore, the proposed experiments test the hypothesis that IGF-1 receptor signaling in the HYP is essential for neuroendocrine regulation of female reproductive function by E2. We will identify the mechanisms and neural sites of IGF-1 regulation of the hypothalamic-pituitary-gonadal axis by determining whether IGF-1 acts directly on the gonadotropin releasing hormone (GnRH) neurons, their afferent inputs, and/or their responsiveness to E2. Finally, we will test the hypothesis that the delayed and attenuated luteinizing hormone (LH) surge that characterizes female rats making the transition to reproductive senescence is causally related to reduced IGF-1 receptor signaling in the aging brain. Specific Aim 1 tests the hypothesis that IGF-1 regulation of the E2-dependent LH surge is mediated at the level of the HYP rather than the pituitary. Specific Aim 2 tests the hypothesis that IGF-1 regulates E2-dependent afferent signals to GnRH neurons. We will determine the effects of brain IGF-1 receptor blockade on GnRH neuronal activation under hormonal conditions that should generate LH surges. We will also determine the effects of brain IGF-1 receptor blockade on E2 regulation of progestin receptors and kisspeptin gene expression in the HYP and on the release of excitatory (glutamate) and inhibitory (GABA) neurotransmitters in medial preoptic area (HYP site of GnRH cell bodies). Specific Aim 3 tests the hypothesis that IGF-1 regulates GnRH neuronal responsiveness to E2 afferent input. We will determine the effects of brain IGF-1 receptor blockade on glutamate, kisspeptin and a1-adrenergic activation of LH release in hormone-primed females. Specific Aim 4 tests the hypothesis that declining levels of bioavailable IGF-1 are causally related to the delayed and attenuated LH surges in middle-aged females undergoing the transition to reproductive senescence. We will determine whether elevating brain IGF-1 restores hormone-dependent LH surges in middle-aged rats, and if so, whether this manipulation also restores E2 regulation of amino acid neurotransmission and of kisspeptin gene expression. These findings may provide insight into the mechanisms underlying premature ovarian failure and reproductive neuroendocrine dysfunction that accompanies diabetes and polycystic ovarian syndrome (PCOS). This could suggest new therapeutic strategies for treating reproductive disorders associated with altered IGF-1 levels, such as PCOS. They could also identify factors whose manipulation might prolong exposure of middle-aged women to the physiological benefits of ovarian steroids